Serum aberrant expression of microRNA-125b-5p and its association with carotid artery stenosis
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Xiaoling Guo
,
Tong Zhang
,
Shaoteng Li
,
Jiahui Guo
,
Lihua Xu
,
Huan Deng
and
Shaojie Yuan
Abstract
Objectives
This study focused on the aberrantly expressed miR-125b-5p and explored its diagnostic and prognostic value in CAS patients.
Methods
218 individuals with informed consent were enrolled including 92 healthy individuals (control) and 126 patients with CAS and they provided blood samples willingly. The miR-125b-5p level was computed through qRT-PCR. For assessing the diagnostic capacity of miR-125b-5p, the receiver operator characteristic (ROC) was adopted, supplemented by correlation analysis. The prognostic performance of miR-125b-5p was appraised with the help of the Kaplan-Meier curve plotted according to 5-year follow-up and multivariate Cox regression.
Results
The expression of serum miR-125b-5p was aberrantly lower in CAS patients than that in the control group. There was a negative correlation between the miR-125b-5p level and the severity of CAS. The ROC curve proved a high credibility in miR-125b-5p diagnosis. The area under the curve (AUC) reached 0.969 with high sensitivity (96.44 %) as well as specificity (86.81 %). Kaplan-Meier curve verified that CAS patients having lower miR-125b-5p were at a higher risk of developing cerebrovascular events (CEs). Both miR-125b-5p and degree of CAS were identified as independent risk factors of developing CEs for CAS patients via multivariate Cox regression analysis.
Conclusions
The serum miR-125b-5p was aberrantly lower in CAS patients. Lower miR-125b-5p possessed high diagnostic along with prognostic value in CAS patients.
Introduction
The carotid artery serves as one of the principal blood vessels supplying the head, particularly the brain. Carotid artery stenosis (CAS) is a clinical condition, primarily caused by arteriosclerotic stenosis [1], and is prevalent among older individuals [2]. It manifests as stenosis or occlusion of the carotid artery lumen. Once the acute occlusion occurs due to CAS, patients may suffer severe insufficient blood and oxygen supply of the brain and even cerebral infarction or brain death [3].
At present, a variety of measures can be used for CAS treatment, including pharmacotherapy, endarterectomy, and endovascular stent implantation [4]. However, the feature of invisibility for CAS can inevitably lead to delayed treatment, which is detrimental to patients. According to the presence or absence of clinical symptoms, CAS is primarily categorized into symptomatic as well as asymptomatic types [2], 5]. Although asymptomatic CAS may occasionally present with transient symptoms such as dizziness, headache, limb numbness, and temporary blindness, these symptoms quickly disappear and therefore it is not easily noticed [6]. CAS has been reported to be responsible for up to 60 % of cerebral infarctions [2]. For patients with severe CAS, the occurrence of cerebral ischemic events can reach nearly 30 % in no more than two years even if effective drug treatment measures are taken [7]. With aging and lifestyle changing, the incidence of CAS is also increasing. Thus, early detection as well as risk prediction contribute to the diagnosis along with enhancing the prognosis in patients.
Numerous reports have demonstrated the involvement and aberrant expression of microRNAs (miRNAs) in the pathophysiological processes of various diseases. Study in macrophages indicates that miR-223, as a global translation regulator of cholesterol efflux as well as inflammatory pathways, can avoid atherosclerosis [8]. Serum miR-28-5p is significantly decreased in patients with asymptomatic CAS and its overexpression in vascular smooth muscle cells exerts an inhibitory effect on the abnormal proliferation as well as migration [9]. Besides, it has also been shown that miR-106b-5p is enhanced in patients with symptomatic CAS and can serve as an indicator for the development of cerebral ischemic events [10].
A large amount of accessible literature has confirmed the extensive implication and regulation of miR-125b-5p in various diseases. For example, a previous study about nasopharyngeal carcinoma has shown the triggering role that miR-125b-5p plays during malignant progression [11]. Moreover, the potential diagnostic performance has been demonstrated in many diseases. For instance, an existing report has demonstrated that reduced serum miR-125b-5p exhibits an excellent diagnostic capability for bladder cancer [12]. According to an endometriosis-related study, the serum miR-125b-5p is an indicator identifying endometriosis from other gynecological disease [13]. Data from acute myocardial infarction (AMI) shows a high diagnostic performance of serum miR-125b-5p [14]. High levels of miR-125b-5p have been shown to improve the function of pulmonary microvascular endothelial cells [15]. The primary pathological basis of CAS is atherosclerosis, which encompasses critical processes such as endothelial injury, inflammatory responses, abnormal proliferation of vascular smooth muscle cells (VSMCs), and vascular remodeling [16]. Accumulating evidence demonstrates that miR-125b-5p plays an essential role in cardiovascular diseases by modulating endothelial function and inflammatory pathways [17]. Specifically, miR-125b-5p can mitigate oxidative stress-induced endothelial cell apoptosis via inhibition of the NF-κB signaling pathway and enhance the survival capacity of vascular endothelial cells [18]. In the context of atherosclerosis, reduced expression of miR-125b-5p may result in excessive inflammatory activation and impaired endothelial repair function [17], contributing to the progression of CAS. Based on these findings, we propose that miR-125b-5p may serve as a potential diagnostic and prognostic marker for CAS by regulating the aforementioned pathological processes. If miR-125b-5p is confirmed as a biomarker, it will help doctors to accurately stratify the risk of patients with CAS and implement personalized treatment plans. However, the expression level and potential value of miR-125b-5p in CAS patients have not been reported.
Here, we focus on the expression degree of miR-125b-5p in serum and investigate its underlying diagnostic and prognostic capacity in CAS.
Materials and methods
Study subjects and sample collection
Permission for this study was granted by the Ethics Committee of Xingtai People’s Hospital prior to research beginning. 218 individuals with informed consent were enrolled including 92 healthy individuals (control) from health examination center without cerebrovascular disease and 126 patients with asymptomatic CAS. All participants were diagnosed with ultrasonography. Vascular ultrasound and CT angiography were applied to determine the degree of CAS. In this research, in accordance with ultrasonography diagnosis, individuals with normal results were classified as control group. Inclusion criteria for CAS: (1) age more than 18 years old, (2) stenosis degree no less than 50 %, (3) no history of stroke, transient ischemic attack or other cardiovascular/cerebrovascular diseases, (4) no severe liver or kidney dysfunction or other systemic diseases. The exclusion criteria: (1) cancer, (2) thyroid dysfunction, (3) receiving antithrombotic therapy and (4) intracranial vascular stenosis. For control group, healthy individuals undergoing physical examination with normal carotid arteries or stenosis <20 % were included. Meanwhile, the exclusion criteria were: (1) metabolic diseases (such as diabetes, hypertension), (2) autoimmune diseases and (3) cardiovascular diseases. We followed 126 CAS patients by telephone for 5 years and recorded individuals who developed CEs including stroke, transient ischemic attack as well as sudden death.
Serum preparation
Once having fasted for 12 h, venous blood of 5 mL was obtained for each participant. Blood samples were standed no less than 1 h before centrifugation of 15 min at 4,000 rpm. The supernatant solution was collected with EP tube to store at −80 °C immediately for subsequent RNA exaction, reverse transcription and quantitative analysis.
qRT-PCR
Total RNA extraction was performed by Trizol under the guidance of the user manual. Then miRcute Plus miRNA firststrand cDNA Kit and miRcute Plus miRNA qPCR Kit from the Tiangen company were served for reverse transcription and subsequent quantitative analysis. The reaction conditions of reverse transcription mainly consisted of twice incubation for 30 min at 16 °C and 42 °C respectively, followed by 85 °C for 5 min. The conditions of quantitative analysis were incubation for 10 min at 95 °C followed by subsequent amplification at the same temperature for 15 s and at 60 °C for 60 s with 40 cycles. The miR-125b-5p level was appraised with 2−ΔΔCt while U6 served as the internal reference.
Statistical analysis
SPSS Statistics 23.0 along with GraphPad Prism 7.0 were applied for data analysis. The outcomes were presented in the form of mean ± SD. Comparison of continuous variables was by Student’s t-test. Moreover, Chi-Square test used to categorical variables. The correlation assessment was conducted by Pearson analysis. Assessment of the 5-year overall incidence of CEs was achieved through Kaplan-Meier with log-rank test. Multivariate Cox regression model was used for assessing the potential independent risk factors of CEs. p<0.05 indicated a statistical variation.
Results
Clinical characteristics of study subjects
The clinical characteristics of enrolled individuals were exhibited in Table 1. The study subjects were classified into control group with 92 participants and CAS group with 126 patients. After comparison between two groups, no difference was found in age (p=0.096), BMI (p=0.936), gender (p=0.413), and FBG (p=0.061). Besides, some characteristics including DBP (p=0.229), TC (p=0.211), and HDL-C (p=0.314), also showed no statistical difference between the control and CAS groups. However, significant differences were exhibited in SBP (p=0.030), TG (p=0.012), and LDL-C (p=0.002). In addition to the above indicators, the degree of CAS patients was also evaluated with a score of 68.45 ± 6.51.
Clinical characteristics of the research population.
| Characteristics | Control (n=92) | CAS (n=126) | p-Value |
|---|---|---|---|
| Age, years | 57.49 ± 7.30 | 59.21 ± 7.63 | 0.096 |
| BMI, Kg/m2 | 22.34 ± 2.44 | 22.31 ± 2.52 | 0.936 |
| Gender, n (%) | 0.413 | ||
| Male | 43 (46.74) | 66 (52.38) | |
| Female | 49 (53.26) | 60 (47.62) | |
| FBG, mmol/L | 6.21 ± 1.10 | 6.52 ± 1.29 | 0.061 |
| SBP, mmHg | 124.23 ± 10.83 | 127.94 ± 14.38 | 0.030 |
| DBP, mmHg | 72.12 ± 6.59 | 80.83 ± 9.48 | 0.229 |
| TC, mmol/L | 4.89 ± 0.96 | 4.73 ± 0.71 | 0.211 |
| TG, mmol/L | 1.35 ± 0.41 | 1.49 ± 0.45 | 0.012 |
| HDL-C, mmol/L | 1.31 ± 0.42 | 1.26 ± 0.37 | 0.314 |
| LDL-C, mmol/L | 2.22 ± 0.45 | 2.61 ± 0.44 | 0.002 |
| Degree of CAS, % | – | 68.45 ± 6.51 | – |
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CAS, carotid artery stenosis; BMI, body mass index; FBG, fasting blood glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL, high density lipoprotein; LDL, low density lipoprotein; Bold font, p<0.05.
Aberrant expression of serum miR-125b-5p in CAS patients
To investigate the possible role of serum miR-125b-5p in CAS disease, its expression was calculated first by qRT-PCR between two groups. The quantitative results indicated a distinct decline of miR-125b-5p in the serum of CAS patients compared to the healthy individuals from control group (Figure 1, p<0.001), implying the probability that reduced miR-125b-5p was linked to CAS.
Relative expression of miR-125b-5p in control (n=92) compared to patients with carotid artery stenosis (CAS, n=126). *** means p<0.001.
The diagnostic performance of miR-125b-5p
Subsequent work was focused on the association of reduced serum miR-125b-5p with CAS disease. Correlation analysis demonstrated the miR-125b-5p was negatively related to the degree of CAS and the lower miR-125b-5p level signified more severe CAS (Figure 2A, r=−0.6038, p<0.0001). In accordance with the expression level of miR-125b-5p, the receiver operator characteristic (ROC) curve was plotted to estimate the diagnostic performance of reduced miR-125b-5p in CAS patients. The Youden index was employed to depict optimal cut-off value (0.725) from the ROC. Furthermore, the area under the curve (AUC) was 0.969, with the sensitivity of 96.44 % and specificity of 86.81 % (Figure 2B).
The diagnostic performance of miR-125b-5p. (A) Pearson’s correlation analysis of relative miR-125b-5p and degree of CAS in CAS patients (n=126, r=−0.6038, p<0.0001). (B) The receiver operator characteristic (ROC) curve of miR-125b-5p. The area under the curve (AUC) was 0.969, with sensitivity of 96.44 % and specificity of 86.81 %.
The prognosis significance of miR-125b-5p
A total of 126 CAS patients were followed up for 5 years. They were classified as high miR-125b-5p expression group (n=66) and low miR-125b-5p expression group (n=60) based on the average miR-125b-5p expression level (0.490) of CAS patients (Figure 3A). The follow-up results indicated that 22 patients developed cerebrovascular events (CEs) and 8 of them were from the high miR-125b-5p expression group while the rest were from the low miR-125b-5p expression group. Specifically, the incidence rate of CEs in the high miR-125b-5p expression group was 12.12 % while it accounted for 23.33 % in the low miR-125b-5p expression group.
The prognosis significance of miR-125b-5p. (A) Kaplan-Meier curves for CAS patients including high miR-125b-5p expression group with eight individuals suffered CEs and low miR-125b-5p expression group with 14 individuals suffered CEs. (B) Relative miR-125b-5p expression in CEs (n=22) and Non-CEs (n=104) groups. ** means 0.001<p<0.05.
Further analysis manifested that the relative miR-125b-5p level in CEs group was obviously depressed compared to the Non-CEs group (Figure 3B, p<0.01). Comparison between two groups showed statistical differences in SBP (p=0.007), TG (p<0.001), LDL-C (p=0.015), miR-125b-5p (p=0.001), degree of CAS (p<0.001) (Table 2). Subsequent multivariate Cox regression analysis proved that patients with high miR-125b-5p expression have a 0.15-fold risk of CEs compared to those with low expression. Meanwhile, patients with severe CAS have a 6.71-fold risk of CEs compared to those with mild CAS. Brifely, miR-125b-5p (HR=0.150, 95 % CI: 0.033–0.680, p=0.014) and degree of CAS (HR=6.710, 95 % CI: 1.495–30.119, p=0.013) were risk factors of developing CEs in CAS patients (Table 3).
Clinical characteristics of the CAS patients.
| Characteristics | CEs (n=22) | Non-CEs (n=104) | p-Value |
|---|---|---|---|
| Age, years | 59.55 ± 7.81 | 59.13 ± 7.64 | 0.820 |
| BMI, Kg/m2 | 22.91 ± 2.79 | 22.19 ± 2.46 | 0.226 |
| Gender, n (%) | 0.109 | ||
| Male | 11 (50.00) | 55 (52.88) | |
| Female | 11 (50.00) | 49 (47.12) | |
| FBG, mmol/L | 6.68 ± 1.26 | 6.49 ± 1.30 | 0.522 |
| SBP, mmHg | 135.41 ± 14.04 | 126.37 ± 14.02 | 0.007 |
| DBP, mmHg | 73.27 ± 6.92 | 73.18 ± 6.40 | 0.955 |
| TC, mmol/L | 4.61 ± 0.65 | 4.76 ± 0.72 | 0.357 |
| TG, mmol/L | 1.81 ± 0.44 | 1.43 ± 0.38 | <0.001 |
| HDL-C, mmol/L | 1.31 ± 0.39 | 1.31 ± 0.43 | 0.988 |
| LDL-C, mmol/L | 2.62 ± 0.48 | 2.37 ± 0.42 | 0.015 |
| MiR-125b-5p | 0.42 ± 0.11 | 0.52 ± 0.13 | 0.001 |
| Degree of CAS, % | 74.99 ± 6.55 | 67.07 ± 5.63 | <0.001 |
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CEs, cerebrovascular events; CAS, carotid artery stenosis; BMI, body mass index; FBG, fasting blood glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL, high density lipoprotein; LDL, low density lipoprotein; Bold font, p<0.05.
Multivariate cox regression analysis for overall survival in CAS patients.
| Variables | Multivariate analysis | ||
|---|---|---|---|
| HR | 95 % CI | p-Value | |
| SBP | 1.892 | 0.770–4.649 | 0.165 |
| TG | 1.827 | 0.680–4.910 | 0.232 |
| LDL-C | 1.056 | 0.434–2.571 | 0.904 |
| miR-125b-5p | 0.150 | 0.033–0.680 | 0.014 |
| Degree of CAS | 6.710 | 1.495–30.119 | 0.013 |
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HR, hazard ratio; CI, confidence interval; CAS, carotid artery stenosis; SBP, systolic blood pressure; TG, triglyceride; LDL, low density lipoprotein; Bold font, p<0.05.
Discussion
Clinically, CAS is visually characteristic of stenosis or occlusion of the carotid artery lumen. Severe CAS can lead to disability and even death and has become an increasing threat to human health. Current diagnostic methods for CAS have obvious shortcomings to be overcome and they are either expensive, invasive in detection with risk of complications, or limited to diagnostic level of the physician. Additionally, the increasing incidence of CAS and its invisibility have also increased the burden for both clinicians and patients. Previous analysis on miRNA profile proves that miRNAs can serve as the biomarker for asymptomatic CAS [19] and significant difference in miRNA expression exists between the symptomatic CAS and the asymptomatic CAS [20]. Therefore, it is necessary and viable to investigate miRNA biomarkers with low cost and simple operation. Our study revealed that the significant downregulation of serum miR-125b-5p is negatively correlated with the severity of CAS and exhibited high diagnostic value. Furthermore, follow-up assessments and multivariate Cox regression analyses indicated that low levels of miR-125b-5p serve as an independent risk factor for the occurrence of CEs in patients with CAS.
Emerging reports of dysregulated miRNAs as biomarkers in a variety of diseases have been reported with the advantages of unique sensitivity and specificity in recent years. For instance, miR-143/-145 has been reported to be essential for the differentiation of vascular smooth muscle cells and can be considered a valuable biomarker in cardiovascular diseases [21]. The reduced miR-204 is reported to be a novel regulator for VSMC calcification and can function as an underlying therapeutic target of medial artery calcification [22]. Here, our data indicated that the serum miR-125b-5p was significantly reduced in CAS patients, compared to healthy individuals. The abnormal expression is consistent with previous reports in many human diseases such as colorectal cancer [23], lung squamous cell carcinoma [24], and endometrial cancer [25]. Current evidence suggests that the downregulation of miR-125b-5p in CAS may be linked to inflammation, a key pathological factor of CAS, and cellular senescence, an important feature of atherosclerosis. Both inflammatory activation and cellular aging can contribute to reduced miR-125b-5p expression, which may impair cellular function and repair [26]. Our results also showed that the down-regulated miR-125b-5p was negatively related to the degree of CAS and showed high diagnostic value in identifying patients with CAS. The diagnostic value of miR-125b-5p has also been proved in many existing reports, including breast cancer [27] and acute ischemic stroke [28]. Our results are consistent with previous findings.
Considering the significantly lower level of miR-125b-5p in CAS group and the diagnostic performance, CAS patients were divided into high miR-125b-5p expression group and low miR-125b-5p expression group to investigate whether the poor prognosis of CAS patients was related to miR-125b-5p level. We plotted the Kaplan-Meier curve according to the 5-year follow-up outcomes and found the relative miR-125b-5p in CAS patients was related to poor prognosis. And CAS patients with lower miR-125b-5p faced more risk of CEs compared to the high miR-125b-5p expression group. Further multivariate Cox regression analysis proved that miR-125b-5p and degree of CAS were independent risk factors of developing CEs, further supporting the association of miR-125b-5p with adverse prognosis. Similar conclusions can also be observed in previous studies. For instance, a follow-up result in AMI shows the obvious correlation between reduced serum miR-125b-5p and 6-month cardiovascular events [14]. Results from hepatocellular carcinoma reveals that the low miR-125b-5p expression level has an obvious correlation with the dismal prognosis [29]. Similarly, in laryngeal squamous cell carcinoma miR-125b-5p is significantly reduced and patients with lower miR-125b-5p levels have worse overall survival [30]. In addition, existing study has also shown that the low miR-125b-5p is identified as an independent prognostic factor of gastric cancer and the prognosis is even worse for patients with lower miR-125b-5p [31]. The above findings highlight the importance of miR-125b-5p as a biomarker for adverse prognosis. As a serum biomarker, miR-125b-5p offers advantages of non-invasive detection, such as convenient testing and strong reproducibility [32], 33]. Its high sensitivity and specificity in diagnosis and prognosis in various diseases confirmed its potential as a clinical biomarker.
There are also research limitations and shortcomings. We evaluated the diagnostic performance of miR-125b-5p, but validation such as cross-validation or independent validation cohort was lacking. An AUC of 0.969 indicated extremely high diagnostic capability, indicating overfitting or an issue with sample selection. This bias on the results may be caused by our relatively small sample size. Regrettably, it is indeed challenging to add an independent validation cohort from the same period at present. In future research, we plan to include an independent validation cohort to verify our findings. In addition, many factors such as lifestyle and smoking may also contribute to the poor prognosis, which were not included during follow-up in our study. Besides, results of our study mainly derived from the data analysis of patients, and the mechanism exploration needed to be carried out to yield more stronger evidence in the feasibility of miR-125b-5p as a biomarker in CAS patients. Therefore, broader research is needed in further study.
We hypothesized that the potential mechanisms of miR-125b-5p in CAS may involve multiple pathways. First, miR-125b-5p could suppress inflammatory responses by inhibiting the NF-κB signaling pathway [34]. The downregulation of miR-125b-5p may result in the overactivation of inflammatory factors, thereby facilitating plaque formation and vascular stenosis. Second, miR-125b-5p may influence CAS by regulating the survival, migration, and angiogenesis of vascular endothelial cells. In patients with CAS, reduced levels of miR-125b-5p may exacerbate endothelial cell injury, impair vascular repair capacity, and further contribute to lumen narrowing. Additionally, our study revealed a negative correlation between miR-125b-5p expression and CAS severity, suggesting that its downregulation may promote excessive activation of VSMCs, leading to heightened inflammatory responses and involvement in vascular remodeling.
Taken together, through experiments and a series of analyses, we confirmed that the serum miR-125b-5p was remarkably decreased in CAS patients compare to healthy individuals. Decreased miR-125b-5p exhibited high diagnostic viability in identifying CAS patients from healthy individuals as well as predicting the CEs occurrence in CAS patients. The miR-125b-5p as well as the degree of CAS were independent risk factors for adverse prognosis in CAS patients. This study yields stronger evidence of the role of miR-125b-5p in CAS.
Funding source: Medical Science Research Project of Hebei
Award Identifier / Grant number: 20201577
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Research ethics: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Xingtai People’s Hospital.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: Authors state no conflict of interest.
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Research funding: This study was funded by Medical Science Research Project of Hebei (20201577).
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Data availability: None declared.
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Supplementary Material
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